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Arch Endocrinol Metab. 2015;59/5

Minimally invasive surgical interventions in the treatment of primary persistent hyperinsulinemic hypoglycemia of infancy

Fahimeh Soheilipour1, Fatemeh Jesmi1, Mohammad Ahmadi1, Abdolreza Pazouki1, Peyman Alibeigi1, Mohammadreza Abdolhosseini1

SUMMARYHyperinsulinemia, diagnosed by laboratory tests, should be diagnosed and treated as soon as pos-sible to prevent fatal complications such as neurological damage. Patients who are resistant to medi-cal therapy should be treated surgically. Minimally invasive surgery, a newly developed approach, is a good choice among surgical procedures to avoid unnecessary extensive pancreatectomy. Here, a 12-year-old boy is presented with diagnosis of hyperinsulinemic hypoglycemia who had recur-rent attacks of hypoglycemia and seizures from infancy. Because of his unresponsiveness to medical therapy and his family’s preference, he underwent laparoscopic pancreatectomy to reduce morbidity and hospital stay. Two years postsurgical follow-up revealed a normo-glycemic state. Arch Endocrinol Metab. 2015;59(5):466-9

1 Minimally Invasive Surgery Research Center, Iran University of Medical Sciences, Tehran, Iran

Correspondence to:Abdolreza Pazouki Minimally Invasive Surgery Research Center,Iran University of Medical Sciences,Tehran, Iranapazouki@yahoo.com

Received on July/28/2014Accepted on Apr/20/2015

DOI: 10.1590/2359-3997000000094

INTRODUCTION

P rimary persistent hyperinsulinemic hypoglycemia of infancy (PHHI), a rare inborn metabolic dis-

ease occurring due to excessive secretion of insulin, is diagnosed by glucose < 60 mg/dL in addition to el-evated plasma insulin (> 2.0 pU/mL). Early diagnosis is important due to probable neurologic sequel, but it is the treatment that seems to be a matter of concern in medicine (1).

PHHI is categorized into focal and diffuse via dif-ferent pathogeneses introduced (2,3). The treatment of choice for adenomatous hyperplasia of pancreatic cells, micro or macro adenoma, is surgical removal (4). On the contrary, diffuse hyperplasia, arisen by islet cell dys-regulation of insulin production, can only be cured by near-total (95%) pancreatectomy as the initial procedure of choice when medical therapy has failed (5). Accord-ing to probable postoperational problems, especially diabetes mellitus due to β-cell dysfunction (6), a biopsy is mandatory to distinguish the two forms of PHHI (7).

Minimally invasive procedures are used increasingly each year to minimize the invasion and side effects in various surgical procedures. Other advantages of mini-

mally invasive procedures include avoidance of large wounds, less postoperative pain, lower rate of morbid-ity, earlier hospital discharge, and cosmetic benefits (8).

Here it is aimed to emphasize the importance of early diagnosis and the role of minimally invasive sur-geries in the diagnosis and treatment of hyperinsulin-emic status.

CASE REPORTThe patient is a 12-year-old obese boy who was admit-ted with recurrent hypoglycemic attacks followed by seizures and speech problems. During his first visit, his hallux was broken due to a recent trauma in a general-ized tonic clonic seizure, and he had a bottle of sugary water in his hand, drinking every few minutes. His birth history was complicated by macrosomia and a birth weight of 5,200 g. His birth height was 60 cm. His mother was not diabetic, and he had no family history of documented hypoglycemia or any other inborn error of metabolism. In physical examination, his height was 117.5 cm (2.5 z score), his weight was 30.2 kg (1.1 z score), and his body mass index was calculated at 27.27 kg/m2. The examination revealed bilateral lipomastia

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and pubertal tanner stage 1 both at gonadal and pubic stages. He was in the 5th grade with a good educational status, having never failed during his education. He had recurrent attacks of hypoglycemia from neonatal period that were diagnosed as PHHI and treated with 10 mg/kg diazoxide daily and frequent feeding.

Hyperinsulinemia was confirmed in this patient by a fasting serum insulin of 9 pU/mL. He had low free fatty acids (both < 1.0 mmol/L), an inappropriate gly-cemic response to intravenous glucagon (> 30 mg/dL rise in serum glucose level), and negative ketones in urine dipstick. Serum lactate, ammoniac, C-peptide, chromatography of serum amino acid and urine sug-ars, morning cortisol, prolactin, and thyroid function tests were all normal (Table 1). Abdominal computered tomographic scan with intravenous and oral contrast did not reveal pancreatic adenoma. Due to his resis-tance to medical therapy and his family’s decision, he was scheduled for surgical intervention. A laparoscopic biopsy was obtained, which revealed diffuse hyperpla-sia of the pancreas; sections showed pancreatic tissue with normal acinar structure, intermixed with islets of Langerhans which are different in size and shape. The cells of the latter showed mild atypia characterized by vesicular nuclei with mild nuclear pleomorphism and enlargement, small nuclei and pale eosinophilic cyto-plasm. No ductuloinsular complexes was identified in multiple sections examined (Figure 1).

Table 1. The results of serum tests of the patient

Serum tests Patient’s result Reference value Unit Method Instrument

Fasting serum insulin 9 2.6-24.5 µIU/mL Electrochemiluminescency Elecsys 2010 Roche HITACHI

Lactate 4 2.5-20 mg/dL Colorimetric BT 3000

Ammoniac 26 Male: 25-94 Female: 19-82

µg/dL Colorimetric BT 3000

C-peptide 2.5 0.8-3.1 ng/mL Electrochemiluminescency Elecsys 2010 Roche HITACHI

Chromatography of serum amino acids and

Normal pattern - - HPLC Kenovera

Chromatography of urine sugars

Normal pattern - - TLC Kenovera

Morning cortisol 32 5-25 µg/dL Electrochemiluminescency Elecsys 2010 Roche HITACHI

Prolactin NL • Males: 2 - 18

• Non-pregnant women: 2 - 29

• Pregnant women: 10 - 209

ng/mL Electrochemiluminescency Elecsys 2010 Roche HITACHI

T4 8 4.5-12.5 µg/dL Electrochemiluminescency Elecsys 2010 Roche HITACHI

T3 132 Adults: 0.8 - 2.0 ng/ml Electrochemiluminescency Elecsys 2010 Roche HITACHI

TSH 2.5 0.5 - 4.70 mIU/L Electrochemiluminescency Elecsys 2010 Roche HITACHI

Figure 1. Pathologic finding: pleomorphism with large nuclei and vesicular nuclei (marked). The cells of the latter showed mild atypia characterized by vesicular nuclei with mild nuclear pleomorphism and enlargement, small nuclei and pale eosinophilic cytoplasm. No ductuloinsular complexes was identified in multiple sections examined.

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Then a laparoscopic pancreatectomy of about 85% of the pancreas was performed (Figure 2). The patient was positioned supine, legs apart, with the surgeon standing between the patient’s legs. The camera holder was on the patient’s right side and the surgeon’s assistant on the patient’s left side. The first trocar was placed into the abdomen above the umbilicus, with open tech-nique, and a 12-mm-trocar about 7 cm at the umbilical level on the left side of the abdomen. One 5-mm-tro-car was inserted 5 cm on the anterior axillary line, one 5-mm-trocar on the mid-clavicular line on the patient’s right side, and the last 5-mm-trocar on the epigastrium.

A 5-mm-ligasure was used for dissection and the gastrocolic meso was first cut to enter the lesser sac. There was no evidence of mass on pancreatic surface. The pancreas was examined with intraoperative laparo-scopic ultrasonography, which detected no adenoma. A biopsy was taken from body of pancreas and sent for frozen section, which confirmed PHHI. So, pan-createctomy was scheduled for this case. The midcolic vein was found and followed to its entrance beneath the pancreas neck and was then dissected beneath it along the superior mesenteric vein until the superior border of the pancreas. Then the neck was transected with a purple EndoGIA tri-stapler, and the body and tail of the pancreas was dissected from its attachments, preserving the splenic artery and vein. After distal pan-createctomy, a corrugated silicone drain was positioned in place.

The patient’s postoperational general condition was good with no complications. The drain was removed five days after the operation. Postsurgical follow-up for two years showed a normo-glycemic state and no oc-currence of diabetes mellitus.

DISCUSSION

Minimally invasive surgical techniques have previously been used in other hyperinsulinemic statuses, like in-sulinomas (9,10). The medical group chose this tech-nique as a result of the patient’s poor drug compliance, which helped him avoid receiving a more invasive inter-vention than needed.

Although medical therapy in combination with fre-quent enteral feeding (11) is the first choice for treat-ment of hyperinsulinemia (12), the response varies widely on clinical subtypes of PHHI, categorized by hyperinsulinemia severity and types of genetic muta-tions causing hypersecretion of insulin (12,13). The risk of hypoglycemic attacks will also rise by increasing the feeding intervals; and as long as older children eat three separate meals, they will be more predisposed to hypoglycemia between the meals; therefore drug thera-py will be less effective in controlling blood sugar with increasing age. On the other hand, older children have less drug compliance, as they may feel ashamed to use drugs in school or in front of their friends, or might resist doctor’s visits, which may altogether cause poorer quality of life for them (14).

Additionally, the response rate of diazoxide, as the cornerstone of drug therapy, is partial and depends on many factors (15). Prevalent complications, such as hypertrichosis, have also been proposed for diazoxide. Serious complications including pulmonary hyperten-sion, heart failure and neutropenia (16), hepatomegaly, severe fluid retention, diffuse edema, congestive heart failure, and respiratory failure requiring mechani-cal ventilation (17) have also been reported. Another problem that exists in our country is the fact that di-azoxide is not always available, due to sanctions.

Studies have assessed the efficacy of various surgical procedures on this rare disease, but few have investigat-ed the minimally invasive approaches. Al-Shanafey and cols. performed laparoscopic pancreatectomy for infancy with a median of 90% extent of resection and revealed many advantages for this procedure including accurate visualization, shorter hospitalization, less postoperative pain, early feeding, and good cosmetic results (18). One year later, he compared ten laparoscopic pancreatecto-mies with open procedure and concluded that the open group needs a higher extent of resection and the laparo-scopic group is able to have earlier feeding (19).

Berends and cols. introduced conventional intraop-erative ultrasonography combined with contact ultra-sonography for better localization of insulinoma (20).

Figure 2. The laparoscopic procedure: There was no evidence of mass on pancreatic surface.

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Because of the small size of the adenomas, radio-logic imaging studies often fail to localize them. Ii-hara and Obara proposed better laparoscopic resection of insulinoma when located in the body or tail of the pancreas (21). Intra-operative frozen section biopsy, requiring less extended pancreatectomy, has been proven to play an essential role in identifying cases of adenoma (22).

The accurate extent of pancreatectomy serves as a pitfall for surgeons, as it may induce diabetes or recur-rent hypoglycemia (23). Ninety-five percent pancre-atectomy is more challenging with more risk of bleed-ing due to the high risk of dissection and ligation of fragile venous branches between superior mesenteric, portal vein and head of pancreas Our surgical team took an intraoperative specimen for frozen section, and performed 85% pancreatectomy to decrease the possi-bility of diabetes mellitus, as 95% has a higher risk of diabetes mellitus. The patient is also still in a normo-glycemic state, two years after the surgery.

Few studies have followed up with patients after the procedure. On the other hand, the laparoscopic approach we performed has rarely been used for this diagnosis. Its major advantages include better visualiza-tion and localization of the mass. An interesting point of this case can also be minimal neurological damage contrary to delayed patient treatment.

In conclusion, minimally invasive pancreatectomy is a good choice for the diagnosis and treatment of hyper-insulinemic hypoglycemia, with better visualization and a less invasive procedure to avoid unnecessary extensive morbidities.

Acknowledgment: we thank the Minimally Invasive Surgery Re-search Center surgery team.

Disclosure: no potential conflict of interest relevant to this article was reported.

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